This renewal application describes a National Cooperative Natural Products Drug Discovery Group (NCNPDDG) dedicated to explorations of novel marine microorganisms and selected marine invertebrates. The specific aims of this proposal remain the isolation and characterization of structurally- and pharmacologically-novel antitumor agents. The long-term goal of this collaborative effort is to develop new anticancer drugs with novel mechanisms of pharmacological action, and with high selectivities toward the most recalcitrant forms of cancer. Despite aggressive efforts to develop new chemotherapeutic treatments for various forms of cancer, current medicines yield low cure rates and undesirable side effects. In the continuing search for more effective anticancer agents, marine organisms have emerged as a promising new resource yielding unusual chemical structures with potent biological activities. The vast diversity, and relatively unexplored nature of marine invertebrates and marine microorganisms, suggests they will continue to represent an important new source of new drugs. The research described herein is a collaborative effort between the Oncology Drug Discovery Group at Bristol-Myers Squibb and marine scientists at the Scripps Institution of Oceanography and The University of Rhode Island. Bristol-Myers Squibb, a leader in the discovery and development of cancer drugs, has a long history of success in this area. They have established a comprehensive system of cancer-relevant screens and predictive biochemical and receptor models. The marine organisms studied will be cultured marine microorganisms and collected invertebrates acquired as part of a continuing research program with the marine laboratory of the Silliman University, a small university located in the central Philippines. The Philippines is the region of highest marine biologically diversity on Earth. Approximately 500 organisms will be collected per year and shipped frozen to 510 for extraction and chemical evaluation. Extracts of invertebrates, and of approximately 1500 microorganism cultures, will be sent to BMS for extensive evaluation in both cell and mechanism based screens. Lead candidates will be selected, and bioassay guided fractionation will be used to isolate active constituents. Bristol-Myers Squibb will thoroughly evaluate new compounds for their chemotherapeutic potential and new agents will be subsequently developed. Ten novel compounds, and in particular one exceptionally interesting agent, discovered during the previous grant period, will be the focus of continued research and development.